bims-stacyt 2019-02-17 papers

Cell Cycle. 2019 Feb 09. 1-12

ARPE-19-derived VEGF-containing exosomes promote neovascularization in HUVEC: the role of the melanocortin receptor 5.

Rosa Maisto, María Oltra, Lorena Vidal-Gil, Natalia Martínez-Gil, Javier Sancho-Pellúz, Clara Di Filippo, Settimio Rossi, Michele D Amico, Jorge Miguel Barcia, Francisco Javier Romero.

ARPE-19 retinal pigment epithelial cells cultured in a medium containing 35 mM D-glucose led to an augmented ROS formation and release of vascular endothelial factor (VEGF)-containing exosomes compared to ARPE-19 cells cultured in a medium containing 5 mM D-glucose (standard medium). Exposing these cells to the melanocortin 5 receptor agonist (MCR5) PG-901 (10-10M), for 9 d reduced ROS generation, the number of exosomes released and their VEGF content. In contrast, incubating the cells with the melanocortin receptor MCR1 agonist BMS-470539 (10-5 M) or with the mixed MCR3/4 agonist MTII (0.30 nmol) did not produce any significant decrease in ROS levels. ARPE-19-derived VEGF-containing exosomes promoted neovascularization in human umbilical vein endothelial cells (HUVEC), an effect that was markedly reduced by PG-901 (10-10M) but not by the MCR3/4 agonist MTII (0.30 nmol) or the MCR1 agonist BMS-470539 (10-5 M). The MCR5-related action in the ARPE-19 cells was accompanied by the increased expression of two coupled factors, cytochrome p4502E1 (CYP2E1) and nuclear factor kappa b (Nf-κB). These are both involved in high glucose signalling, in ROS generation and, interestingly, were reduced by the MCR5 agonist in the ARPE-19 cells. Altogether, these data suggest that MCR5 is a modulator of the responses stimulated by glucose in ARPE-19 cells, which might possibly be translated into a modulation of the retinal pigment epithelium response to diabetes in vivo.

Keywords: Diabetes; exosomes; melanocortin receptors; oxidative stress; vasculogenesis

DOI: https://doi.org/10.1080/15384101.2019.1568745

Int J Biol Macromol. 2019 Feb 08. pii: S0141-8130(18)36945-9. [Epub ahead of print]

Circular RNA circPTK2 regulates oxygen-glucose deprivation-activated microglia-induced hippocampal neuronal apoptosis via miR-29b-SOCS-1-JAK2/STAT3-IL-1β signaling.

Huilin Wang, Zheng Li, Jingyan Gao, Qingwu Liao.

Oxygen-glucose deprivation (OGD)-activated microglia contribute to neuronal apoptosis via releasing pro-inflammatory cytokines, and some miRNAs have been reported to be involved in this process. Circular RNAs (circRNAs) have been reported to function as miRNA sponges, but it remains unknown whether and how circRNAs contribute to OGD-activated microglia-induced neuronal apoptosis. Here, we investigated the function and relationship of miR-29b and circPTK2 in OGD-activated microglia-induced neuronal apoptosis. We found upregulation of TNF-α and IL-1β, and downregulation of miR-29b in OGD-activated microglia. miR-29b inhibited OGD-activated microglia-induced neuronal apoptosis. Meanwhile, miR-29b promoted SOCS-1 expression, and suppressed JAK2/STAT3 signaling. In addition, inhibition of JAK2/STAT3 signaling downregulated IL-1β expression, while upregulation of miR-29b or SOCS-1 also inhibited IL-1β production. IL-1β was confirmed to be an apoptosis inducer of hippocampal neurons. Moreover, either SOCS-1 upregulation or blockade of JAK2/STAT3 signaling suppressed OGD-activated microglia-induced neuronal apoptosis. These data suggest that miR-29b inhibits OGD-activated microglia-induced neuronal apoptosis via inducing SOCS-1 expression, blocking JNK2/STAT3 signaling, and inhibiting IL-1β production. circPTK2 was confirmed to inhibit miR-29b expression in OGD model by directly binding to miR-29b. Function assay showed that circPTK2 regulated microglia-induced neuronal apoptosis via sponging miR-29b. Collectively, these findings suggest that circPTK2 regulates OGD-activated microglia-induced neuronal apoptosis via miR-29b-SOCS-1-JAK2/STAT3-IL-1β signaling.

Keywords: Apoptosis; Hippocampal neuron; Microglia; Oxygen-glucose deprivation; circPTK2; miR-29b

DOI: https://doi.org/10.1016/j.ijbiomac.2019.02.041

Stem Cell Res Ther. 2019 Feb 13. 10(1): 58

Immunoregulatory potential of mesenchymal stem cells following activation by macrophage-derived soluble factors.

Laura Saldaña, Fátima Bensiamar, Gema Vallés, Francisco J Mancebo, Eduardo García-Rey, Nuria Vilaboa.

BACKGROUND: Immunoregulatory capacity of mesenchymal stem cells (MSC) is triggered by the inflammatory environment, which changes during tissue repair. Macrophages are essential in mediating the inflammatory response after injury and can adopt a range of functional phenotypes, exhibiting pro-inflammatory and anti-inflammatory activities. An accurate characterization of MSC activation by the inflammatory milieu is needed for improving the efficacy of regenerative therapies. In this work, we investigated the immunomodulatory functions of MSC primed with factors secreted from macrophages polarized toward a pro-inflammatory or an anti-inflammatory phenotype. We focused on the role of TNF-α and IL-10, prototypic pro-inflammatory and anti-inflammatory cytokines, respectively, as priming factors for MSC.METHODS: Secretion of immunoregulatory mediators from human MSC primed with media conditioned by human macrophages polarized toward a pro-inflammatory or an anti-inflammatory phenotype was determined. Immunomodulatory potential of primed MSC on polarized macrophages was studied using indirect co-cultures. Involvement of TNF-α and IL-10 in priming MSC and of PGE2 in MSC-mediated immunomodulation was investigated employing neutralizing antibodies. Collagen hydrogels were used to study MSC and macrophages interactions in a more physiological environment.
RESULTS: Priming MSC with media conditioned by pro-inflammatory or anti-inflammatory macrophages enhanced their immunomodulatory potential through increased PGE2 secretion. We identified the pro-inflammatory cytokine TNF-α as a priming factor for MSC. Notably, the anti-inflammatory IL-10, mainly produced by pro-resolving macrophages, potentiated the priming effect of TNF-α. Collagen hydrogels acted as instructive microenvironments for MSC and macrophages functions and their crosstalk. Culturing macrophages on hydrogels stimulated anti-inflammatory versus pro-inflammatory cytokine secretion. Encapsulation of MSC within hydrogels increased PGE2 secretion and potentiated immunomodulation on macrophages, attenuating macrophage pro-inflammatory state and sustaining anti-inflammatory activation. Priming with inflammatory factors conferred to MSC loaded in hydrogels greater immunomodulatory potential, promoting anti-inflammatory activity of macrophages.
CONCLUSIONS: Factors secreted by pro-inflammatory and anti-inflammatory macrophages activated the immunomodulatory potential of MSC. This was partially attributed to the priming effect of TNF-α and IL-10. Immunoregulatory functions of primed MSC were enhanced after encapsulation in hydrogels. These findings may provide insight into novel strategies to enhance MSC immunoregulatory potency.

Keywords: Cytokines; Hydrogels; Immunomodulation; Macrophage polarization; Mesenchymal stem cells; Priming; Tissue repair

DOI: https://doi.org/10.1186/s13287-019-1156-6

Int J Mol Sci. 2019 Feb 11. pii: E749. [Epub ahead of print]20(3):

Hypoxia Induced ER Stress Response as an Adaptive Mechanism in Cancer.

Sandhya Chipurupalli, Elango Kannan, Vinay Tergaonkar, Richard D'Andrea, Nirmal Robinson.

It is evident that regions within tumors are deprived of oxygen, which makes the microenvironment hypoxic. Cancer cells experiencing hypoxia undergo metabolic alterations and cytoprotective adaptive mechanisms to survive such stringent conditions. While such mechanisms provide potential therapeutic targets, the mechanisms by which hypoxia regulates adaptive responses-such as ER stress response, unfolded protein response (UPR), anti-oxidative responses, and autophagy-remain elusive. In this review, we summarize the complex interplay between hypoxia and the ER stress signaling pathways that are activated in the hypoxic microenvironment of the tumors.

Keywords: HIF-1; UPR; cancer; endoplasmic reticulum; hypoxia; stress-response

DOI: https://doi.org/10.3390/ijms20030749

Cancer Immunol Immunother. 2019 Feb 13.

Tumor infiltrating mast cells determine oncogenic HIF-2α-conferred immune evasion in clear cell renal cell carcinoma.

Ying Xiong, Li Liu, Yu Xia, Yangyang Qi, Yifan Chen, Lingli Chen, Peipei Zhang, Yunyi Kong, Yang Qu, Zewei Wang, Zhiyuan Lin, Xiang Chen, Zhuoyi Xiang, Jiajun Wang, Qi Bai, Weijuan Zhang, Yuanfeng Yang, Jianming Guo, Jiejie Xu.

PURPOSE: Hypoxia-inducible factor 2α (HIF-2α) overexpression leads to activation of angiogenic pathways. However, little is known about the association between HIF-2α expression and anti-tumor immunity in clear cell renal cell carcinoma (ccRCC). We aimed to explore how HIF-2α influenced the microenvironment and the underlying mechanisms.EXPERIMENTAL DESIGN: We immunohistochemically evaluated immune cells infiltrations and prognostic value of HIF-2α expression in a retrospective Zhongshan Hospital cohort of 280 ccRCC patients. Fresh tumor samples, non-tumor tissues and autologous peripheral blood for RT-PCR, ELISA and flow cytometry analyses were collected from patients who underwent nephrectomy in Zhongshan Hospital from September 2017 to April 2018. The TCGA KIRC cohort and SATO cohort were assessed to support our findings.
RESULTS: We demonstrated that ccRCC patients with HIF-2αhigh tumors exhibited reduced overall survival (p = 0.025) and recurrence-free survival (p < 0.001). Functions of CD8+ T cells were impaired in HIF-2αhigh patients. In ccRCC patients, HIF-2α induced the expression of stem cell factor (SCF), which served as chemoattractant for mast cells. Tumor infiltrating mast cells impaired anti-tumor immunity partly by secreting IL-10 and TGF-β. HIF-2α mRNA level adversely associated with immunostimulatory genes expression in KIRC and SATO cohorts.
CONCLUSIONS: HIF-2α contributed to evasion of anti-tumor immunity via SCF secretion and subsequent recruitment of mast cells in ccRCC patients.

Keywords: Clear cell renal cell carcinoma; Hypoxia-inducible factor 2α; Immune evasion; Stem cell factor; Tumor infiltrating mast cells

DOI: https://doi.org/10.1007/s00262-019-02314-y

Annu Rev Physiol. 2019 Feb 10. 81 535-560

Regulation of Blood and Lymphatic Vessels by Immune Cells in Tumors and Metastasis.

Massimiliano Mazzone, Gabriele Bergers.

Research over the last decades has provided strong evidence for the pivotal role of the tumor-associated blood and lymphatic vasculature in supporting immunoevasion and in subverting T cell-mediated immunosurveillance. Conversely, tumor blood and lymphatic vessel growth is in part regulated by the immune system, with infiltrating innate as well as adaptive immune cells providing both immunosuppressive and various angiogenic signals. Thus, tumor angiogenesis and escape of immunosurveillance are two cancer hallmarks that are tightly linked and interregulated by cell constituents from compartments secreting both chemokines and cytokines. In this review, we discuss the implication and regulation of innate and adaptive immune cells in regulating blood and lymphatic angiogenesis in tumor progression and metastases. Moreover, we also highlight novel therapeutic approaches that target the tumor vasculature as well as the immune compartment to sustain and improve therapeutic efficacy in cancer.

Keywords: angiogenesis; antiangiogenic therapy; immunotherapy; innate and adaptive immune cells; metabolism; tumor blood and lymphatic vessels

DOI: https://doi.org/10.1146/annurev-physiol-020518-114721